Journal Article

GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes

Smits, Mark M., Joles, Jaap A., Tonneijck, Lennart, Hoorn, Ewout J., van Raalte, Daniël H., Kramer, Mark H. H., van Baar, Michaël J.B., Muskiet, Marcel H. A.

2017

Overview

Key Points The incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gut-derived hormones that potentiate insulin secretion and contribute to glucose metabolism through a wide range of physiological actions Inhibitors of the incretin-inactivating enzyme dipeptidyl peptidase 4 (DPP-4) and DPP-4-resistant injectable GLP-1 receptor agonists have been developed for the treatment of hyperglycaemia in type 2 diabetes mellitus (T2DM) GLP-1 and other gut-derived hormones might directly and/or indirectly regulate electrolyte and fluid homeostasis by influencing feeding and drinking behaviour as well as electrolyte transport in the kidneys and gastrointestinal tract GLP-1 receptor (GLP-1R) agonists and DPP-4 inhibitors increase natriuresis in T2DM, possibly through overlapping and distinct mechanisms, and might slightly improve renal haemodynamics in the setting of diabetes-related glomerular hyperfiltration Incretin-based therapies seem to directly influence renal physiology and have indirect metabolic and haemodynamic actions that might reduce renal risk in T2DM; considerable interest exists in identifying these glucose-independent renoprotective actions Data from clinical trials suggest that GLP-1R agonists and, to a lesser extent, DPP-4 inhibitors marginally improve surrogate renal end points, plausibly beyond the effects of improved glycaemic control The incretin hormone glucagon-like peptide 1 (GLP-1) has been implicated in the gut–renal axis and incretin-based therapies might reduce the burden of diabetic kidney disease. Here, the authors review the physiological roles of GLP-1, the potential renoprotective mechanisms of incretin-based therapies and the available renal outcome data from clinical trials. The gastrointestinal tract — the largest endocrine network in human physiology — orchestrates signals from the external environment to maintain neural and hormonal control of homeostasis. Advances in understanding entero-endocrine cell biology in health and disease have important translational relevance. The gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) is secreted upon meal ingestion and controls glucose metabolism by modulating pancreatic islet cell function, food intake and gastrointestinal motility, amongst other effects. The observation that the insulinotropic actions of GLP-1 are reduced in type 2 diabetes mellitus (T2DM) led to the development of incretin-based therapies — GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors — for the treatment of hyperglycaemia in these patients. Considerable interest exists in identifying effects of these drugs beyond glucose-lowering, possibly resulting in improved macrovascular and microvascular outcomes, including in diabetic kidney disease. As GLP-1 has been implicated as a mediator in the putative gut–renal axis (a rapid-acting feed-forward loop that regulates postprandial fluid and electrolyte homeostasis), direct actions on the kidney have been proposed. Here, we review the role of GLP-1 and the actions of associated therapies on glucose metabolism, the gut–renal axis, classical renal risk factors, and renal end points in randomized controlled trials of GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/4020/2741 / 692/699/1585/2759/1419 / 692/699/2743 / 692/700/565/1436 / Blood Glucose - drug effects / Blood Glucose - metabolism / Care and treatment / Development and progression / Diabetes / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - physiopathology / Diabetic Nephropathies - drug therapy / Diabetic Nephropathies - metabolism / Diabetic Nephropathies - physiopathology / Dipeptidyl-Peptidase IV Inhibitors - pharmacology / Gastrointestinal hormones / GLP-1 receptor agonists / Glucagon-Like Peptide 1 - physiology / Glucose / Glucose metabolism / Health aspects / Homeostasis / Humans / Hyperglycemia / Hyperglycemia - drug therapy / Hyperglycemia - metabolism / Hyperglycemia - physiopathology / Hypoglycemic Agents - pharmacology / Incretins - pharmacology / Kidney / Medicine & Public Health / Metabolism / Nephrology / Physiological aspects / Physiology / review-article / Risk Factors / Type 2 diabetes